Field of Invention
The inventive subject matter relates to Plasmodium falciparum circumsporozoite protein (CSP) polypeptides containing HLA-restricted CD8+ T-cell epitopes. The inventive polypeptides or epitopes can be utilized in assays to evaluate candidate vaccines to malaria. Additionally, the polypeptides can be incorporated into vaccine formulations against P. falciparum. 
Background Art
Malaria is caused by the vector borne organism Plasmodium spp. The parasite has a complex lifecycle involving stage specific expression of proteins. These proteins can be expressed at different stages or be specific to stages. Malaria is an extremely important disease, with over 3 billion people living in malaria endemic areas. Over 1 million deaths are attributable to malaria per year. The emergence of drug resistant strains has compounded the problem of treating the disease. Unfortunately, no FDA-approved vaccine exists.
The entire genomic sequence of P. falciparum has been sequenced (Bowman et al., Nature, 400: 532-538 (1999), Gardner, et al., Nature, 419: 498-511 (2002)). The rodent malaria parasite, P. yoelii has also been sequenced (Carlton et al., Nature, 419: 512-519 (2002)). Despite this, however, the development of efficacious anti-malaria vaccines has been severely hampered by the paucity of promising antigens. As such, no FDA-approved vaccine to this agent exists.
Sterile protective immunity to malaria induced by experimental immunization with irradiated sporozoites is thought to be mediated by CD4+ and CD8+ T cells directed against malaria antigens expressed on the surface of infected hepatocytes and perhaps anti-sporozoite antibodies (Agnandji, et al., N. Engl. J. Med., 365: 1863-75 (2011)). Naturally acquired anti-malarial immunity is mediated primarily by antibodies to blood-stage parasites with T cell responses possibly providing a contribution. Both CD4+ and CD8+ T cells are needed for optimal effector cell functions. Furthermore, the development of immunological memory (Beeson, et al., Trends Parasitol 24: 578-584 (2008)) and T cell responses is known to be genetically restricted.
The circumsporozoite protein (CSP) is the main antigenic component of the RTS,S vaccine that has demonstrated ≈50% efficacy in Phase 3 trials in Sub-Saharan Africa (Agnandji, et al., N. Engl. J. Med., 365: 1863-75 (2011)). While RTS,S induces anti-CSP antibodies and CD4+ T cell responses thought to be associated with protection (Moorthy and ballou, Malar J., 8: 312 (2009)), CD8+ T cell responses to CSP have not been consistently demonstrated in RTS,S vaccinated individuals (Moorthy and ballou, Malar J., 8: 312 (2009)), which may limit its ability to target the liver stage of Plasmodium. It has been suggested that vaccine strategies promoting the induction of CD8+ T cell responses to RTS,S, such as priming with adenovirus vectored vaccines, might improve protection.